The development of liver diagnostic procedures (biopsy, endoscopy, sonography etc.) has enabled the earlier and more exact recognition of liver disorders. The early diagnosis should be followed by timely intervention taking into consideration the progredial feature of the disease, as there are substantially fewer therapeutical methods for the treatment of the disease than diagnostic procedures to discover it. Simultaneously the prevalence of liver disorders has increased rapidly in the last decades.
According to epidemiologic tests it has become obvious that the number of liver disorders shows an increasing tendency (Statistic Year-Book of 1949 to 1955; issued by the Central Statistical Office, Budapest, 1957; Statistic Year-Book of 1970, issued by the Central Statistical Office, Budapest, 1971). It shows, that three times as many people died from liver cirrhosis in 1977 than in 1955.
A large number of those dying as a result of liver cirrhosis die at the age of between 40 and 59, i.e. during working age. Thus in 1970 35%, whereas in 1978 41% of the patients died at the age of 40 to 50 due to liver cirrhosis.
These data are in accordance with the conclusions drawn from mortality statistics relating to 26 countries on 4 continents, indicating that the prevalence of liver cirrhosis increased worldwide to such an extent, that one can speak of an epidemic of liver cirrhosis.
Among the causative factors primarily alcoholism appears to be responsible for this intensive spread of liver diseases. The most frequent types of liver disorders are fatty liver, alcoholic hepatitis and alcoholic cirrhosis.
The ultimate therapeutic treatment of liver disorders cannot be considered to have been discovered [Orvosi Hetilap 112:386 (1971); Z. arztl. Fortbildung, 68, 234 (1974); Knoll: Gyogyszertan (1974); Szekeres: Orvosi gyogyszertan (1980)].
The cause inducing the liver damaging process is irrelevant; it can be said as a fundamental principle, that the result of the pathological process is determined by the equilibrium between the deleterious effect of the noxious agent (virus, alcohol) and the positive effect of the regenerating activity of liver tissue. Nowadays there is no possibility to eliminate the noxious agents, especially in the case of developed and progrediated liver diseases. The only realistic aim to be achieved by the therapeutic treatment is to enhance the natural regenerating property of liver tissue. Knowing the complexity of liver function, this treatment cannot be in the form of a monotherapy.
The success of polytherapeutic treatments depends on finding pharmaceutical compounds for the preparation of the pharmaceutical combinations capable of influencing the basic pathological process. Possessing such compounds one can work out such combinations which may be suitable for the planning of pharmaceutical compositions of several "points of attack".
The precursors of amino acids can be considered such pharmaceutical compounds for treatment of liver disorders [Dtsch., Med., Wschr., 78 1331 (1953); Dtsch., Med., Wsch., 81 573 (1956)]. However, the nucleotides or nucleosides in question are generally unable to penetrate through the cell-membrane and they are often toxic as well [Angew. Che., 82, 730 (1970); J. Med. Chem. 15, 1334 (1972)]. The problem is increased by the fact, that the preparation of these compounds is very expensive and complicated.
Therefore the search has been directed to such chemical structures which can easily penetrate into the cell and can there be transformed into nucleotides.
It is wellknown in the art, that the fatty liver induced by alcohol, characterized by triglyceride accumulation and ATP decrease, cannot be normalized by administration of guanine, GTP or ATP [Arch., Int. Pharmacodyn. 232, 302 (1978)]. Though the fatty liver thus induced and the ATP decrease can be normalized by intraperitoneal adenine (6-aminopurine) administration, a part of the 6-aminopurine is transformed into 8-oxyadenine and 2,6-dioxyadenine metabolites, which severely damage the kidney-function [J. Pharmacol. exper. Ther. 140, 20 (1952)].
The administration of the nucleotide precursor orothic acid also leads to the disorder to the lipid metabolism of liver and results in fatty liver [J. Biol. Chem. 238, 2464 (1963)]. This fatty liver as well as the fatty liver caused by ethionine can be normalized by the administration of adenine (6-aminopurine), but it cannot be used for therapeutic purposes due to its nephrotoxic effect referred above.
The purine precursor 5-aminoimidazole-4-carboxamide (AICA) [Science, 112, 634 (1950); J. Biol. Chem. 196, 513 (1952)] was used for therapeutic treatment [J. Med. Sci. 15, 171 (1964)] in the form of its salt formed with orothic acid under the trade name of Aicorat.RTM. [Ann. Histochim. 14, 79 (1969)].
Tha Aicorat.RTM. was not therapeutically effective because the orothic acid itself is a liver damaging agent [J. Biol. Chem. 238, 2464 (1963)], thus in the orothic acidic salt of AICA the advantageous effect of AICA was nullified by the harmful effect of the other component.
We thus targeted our efforts at finding such imidazole carboxamide derivatives which possess the advantageous effects of purine precursor but are free of the negative effects reported in the case of Aicorat.RTM..
Exp. Path 15, 271-287 (1978) reports on the advantageous pharmacological properties of 5-aminoimidazole-4-carboxamide orthophosphate (further: AICA-phosphate) in the treatment of liver artificially damaged by carbon tetrachloride.
It is known, that AICA-phosphate can be prepared by reacting 2-amino-2-cyano acetamide with formamidine ortho phosphate (Hungarian patent specification No. 164,397). The raw AICA-phosphate thus obtained is not suitable for therapeutical purposes.